Eteplirsen and the rise of patient participation in FDA drug approvals.

A long road traveled

Let me first preface this article with the admission that the FDA drug approval process is not, or anywhere near perfect. Also, I do feel conflicted as DMD is a devastating disease with little to no treatment. I do feel for the children, and their family, who are desperately searching for any treatment possible. The recent decision to grant accelerated approval, although conditional, is worrying. Have we entered the age of FDA drug approvals that are no longer decided on the quality of their research, but on the emotional appeal of the patients that may benefit from the drug’s approval?

Sarepta has gone through quite the battle to have their most high profile drug, Eteplirsen, approved for sale to patients. But on April of this year, in front of a standing room only crowd of Eteplirsen supporters and DMD patients, the FDA drug advisory board denied approval to Sarepta’s wonder drug. In a 7 to 3 vote, the panel advised that Sarepta had not met the FDA requirements for well controlled studies to demonstrate the drug’s efficacy.

A case study in small sample sizes and poor placebo control

The key data Sarepta had presented to the FDA board was a single study of 12 cohorts with DMD that was conducted over the course of a year. The study did follow the gold standard double-blind placebo-controlled methodology, although 24 weeks in the placebo cohorts were randomized to drug. Small sample sizes are obviously unavoidable when it comes to rare genetic disorders. To put it in perspective, if the FDA had voted to approve Eteplirsen, it would have set a record for the least amount of clinical data of its efficacy in the history of FDA approvals.

Not only did this single study suffer from an extremely small sample size, it also showed marginal efficacy. DMD treatments are verified, primarily, by a test called the 6MWT (6 Minute Walk Test). During this trial two of the boys that received the lower dose of Eteplirsen lost the ability walk very quickly after being recruited into the trial. The rest showed moderate (but statistically significant) improvement in the 6MWT compared to placebo.

Although the study showed statistically significant improvement in 6 of the cohorts, what does this tell us? To me, it’s an indication that the drug could be effective in slowing down or halting DMD in young boys, the key word being could, but more study is warranted. To, once again, put into perspective the situation the FDA was facing, A competitor, GlaxoSmithKline, which was developing a similar drug, did a randomized trial involving 186 boys, one third of whom were given a placebo. That drug, now owned by BioMarin Pharmaceutical, did not prove effective in that study and failed to win FDA approval.

The FDA advisory board suggested to Sarepta to repeat the study but with adequate placebo controls and to present the data again for another evaluation. But the company argued that it would be unethical and impractical to do so, since early hints of effectiveness meant that parents would no longer enroll their sons in a trial where they might not get the drug.

A paradigm shift in FDA approvals of new drugs

Even with the poorly controlled trial complete with its minuscule sample size, in September of this year the FDA granted accelerated approval to Sarepta to produce and administer its new drug. This isn’t the same as full approval as it comes with contingencies where Sarepta still needs to show that the drug is effective.

On one hand this is amazing news for DMD sufferers as it gives them a glimmer of hope, but on the other hand the drug is astronomically expensive and has extremely limited proof of efficacy past placebo. The treatment will cost in the neighborhood of $300,000 annually, with insurance companies picking up the tab, except for Anthem who already announced they would not cover the drug as they are not convinced of its efficacy past placebo.

With the accelerated approval, it is hard to argue that this may be the first time the FDA has relied more on the lobbying of patients, their family, and others rather than the science behind the medication. Along with what may be the largest lobbying campaign for a drug approval in history, supporters of the drug recruited 109 members of congress to pen a letter to the FDA calling for its approval.

Where are we now?

At this point in time, Sarepta has been cleared to begin treating patients with their drug. But at the same time, they are obligated to provide the FDA with additional clinical data over the next few months. If this additional data is not placebo controlled, or even blinded, then does it even qualify for sufficient evidence? Only time will tell if the FDA finally approves the drug once and for all, but if they do, it will be a paradigm shift in how drugs are approved. That could be a good thing, but it could also mean a dramatic shift in the quality of drugs entering the market as the bar for clinical evidence has been lowered substantially as long as sufficient lobbying is performed.

While an open debate about what we, as tax payers and potential patients, would like the FDA drug approval process to achieve, varying the standards applied based on need or emotional appeal is bad for patients. Under current regulation, Eteplirsen falls well below the bar for approval on the currently available data. I do hope I am wrong. I hope that Eteplirsen is a miracle drug and changes DMD sufferers lives forever. I hope Sarepta is successful in obtaining the data they need to get the drug approved once and for all. I don’t, however, like the direction the FDA drug approvals process is heading.